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Memory effect of chirality in the photocyclization of modified dipeptides
TETRAHEDRON LETTERS Tetrahedron Letters 39 (1998) 3685-3688
Pergamon
Memory Effect of Chirality in the Photocyclization of Modified Dipeptides
Stefan Sauer, Andreas Schumacher, Fr6d6rique Barbosa and Bernd Giese*
Department of Chemistry, Universityof Basel, St. Johanns-Ring 19, CH-4056 Basel, Switzerland
Received 27 February 1998; accepted 17 March 1998
Abstract: Photocyclizations of dipeptides 5 and 8 occur mainly with retention of configuration at the stereogenic center of alanine. This memory effect of chirality is explained by a hindered rotation in the two intermediate biradicals 9 and 10 that slows down the equilibration of the radicals. © 1998 Elsevier Science Ltd. All rights reserved.
Recently, we have demonstrated that photochemical cyclizations of the modified dipeptides 1 into glycine are regio- and stereoselective and follow a remarkable asymmetric induction if valine is the inducing amino acid. 1 Intermediates are biradicals 2 that are formed in a regioselective H-abstraction step from the triplet state of the phenyl ketone. After the triplet-singlet intersystem crossing the biradical 2 cyclizes and yields 3 as main product.
O,~Ph
HO.~Ph Ph
(~ H2)n hv ~N~ IC02Me 0
R 1
.. .yco2Me
,
0
R
O
R
O
3
2
n=l
Scheme I
HO
(~H2)n
n=2
10
7.4
R
4 :
1 (R=Pr j,51%)
:
1 (R = Pri, 67"/o)
We have now observed that selective photochemical cyclization reactions can occur also if both amino acids of the dipeptides are substituted) Thus, the modified ala-val dipeptide 5 yields mainly pyrrolidinone 6 as cyclization product. 3 The isomer ratio 6:7 of 16:1 at-15°C demonstrates that the C,C-bond formation occurs with high retention at the stereogenic center of alanine. In order to check whether this stereoselectivity is caused by the asymmetric induction of valine we have synthesized the R,S-ala-val dipeptide 8. This dipeptide also cyclized with high stereoselectivity, but now isomer 7 was the main cyclization product (6:7, <1:20, 0°C). Again, the product with retention of configuration at the alanine was formed preferentially.4
0040-4039/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved. PII." S0040-4039(98)00621-2
3686
Ph HO hv
BocHN'~Ny
cO2Bn
O
HC)
B ° c H N ' " " " ~ N ~ C O 2 B n + BocHN~ ~ , , ~I N v C O 2 B n -!
Pri
O
5
0% O
-. Pd
h v i=,
8
:
1 (20°C, CH3OH, 50%)
16
:
1 (-15°C, CH3OH)
4
:
1 (0°C, CH2CI2)
BOCHN'""~Ny c02Bn+= .
O
HO Ph.,..~ BocHN,~ / \ " " ~ / N V C O 2 B. n _
Pd
O
6
Pd
7
1 <1
Scheme 2
15ri
7
HO P h ~
CO2Bn
-
O
6
Ph
BocHN,/~Nv
"
Pd
: :
10 (20°C, CH2CI2,35%) 20 (0°C, CH2CI2)
The experimental results show that the intermediate biradicals formed from dipeptides 5 and 8 must differ from each other during their reaction time scale and that they possess a memory of the configuration of their precursors. A possible explanation of this memory effect5"6is given in Scheme 3: The H-abstraction by the photochemical excited ketone 5 *7 leads to biradical 9 in which the hydroxybenzyl radical is positioned at the
re-
side of the alanyl radical. If the triplet-singlet intersystem crossing 8 and the subsequent radical combination is faster than the rotation around the N - C H 2 bond (9 ~ 10), then the cyclized product 6 with retention of configuration is formed preferentially. In a similar way, dipeptide 8 would yield 7 as main cyclization product.
Ph
Ph
hv 5
( =
hv
pr i
0
H
5*
p i
0
8
~
H
8*
1 HO
/
6
"
BocHN"
""'I ~NI .,,,pri ~J~ " ~ C O 2 B n O H 9
' " ~i N Ph
i ,,,Pr BoeHN"H(~"'~CO2Bn O H
"
7
10
Scheme 3
In biradicals 9 and 10 the rotation around the N - C H 2 bond is presumably hindered by the alkyl substituents of the amino acids. In order to check this we synthesized modified dipeptides 11 and 14 containing
3687
glycine or selectively deuterated glycine9 as one of the amino acids. The photochemical cyclization of 11 led to products 12 and 13 in a l'l ratio, t° Thus, the memory effect of chirality is completely lost. Obviously, the equilibration of the intermediate biradicals is faster than the triplet-singlet interconversion with subsequent cyclization.
Ph O:==~
BocHN~N~
H~h,,.~
P~,?,..~
CO2Bn chHV(~I2B o c H N ~ / N ~ C O 2 Bn + B°cH~ N , ~ J ~ C O 2 B n
O
O
11
12
O 1
:
1
Ph
HO Ph,,,..~-.~ ZHN~ I \
0 HO,,,..~.~r~~ D%~ IN..CO2Bn hv N~,~,/~Nv ZHN" y y CH2CI2 ZH "" C02Bn 0 Pri 0 Pd Scheme4
14
15
10
13
D,~-Nv C02Bn 0
:
1
Pd
16
The photochemistry of selectively deuterated 9 dipeptide 14 is also very instructive. In Scheme 4 only the deuterated cyclization products following the H-abstraction are shown. The preferred formation of the pyrrolidinone 15 is in accord with the asymmetric induction found for the undeuterated dipeptide 1 (Scheme l ) l but the H-abstraction and the C,C bond formation occur on opposite sides of the glycine. This means that the asymmetric induction by valine (1-~3 or 14--->15) and not the memory effect of chirality governs the photocyclization of 14. These experiments offer strong support for the explanation that the memory effect is caused by a hindered rotation around the N-CH 2 bond that slows down the equilibration between 9 and 10. Therefore, the intersystem crossing with subsequent cyclization is faster than the equilibration, and the biradicals 9 and 10 preserve the memory of the alanine chirality. That this memory effect could be a general phenomenon in photocyclizations of substituted peptides with bulky amino acids is demonstrated by the cyclization of dipeptide 16 which led mainly to compound 17 with retention of the chiral center of proline. 11.12 Ph
==•N~CO2Bn
O
,
Boc
,, 0 16
Me
hv / 20°C~ CH C, 50%
Hp~h~,,.. ~~N.,..jCO2Bn+ '0 °
HO=
,,
_ e
17
..y/CO2Bn
(/" I 0
Boc 5
:
1
_, Me
18
Scheme 5
Acknowledgments: This work was supported by the Swiss National Science Foundation. We thank Prof. M. Zehnder and M. Neuburger for the crystal structure analysis and Dr. Pablo Wessig for very helpful discussions.
3688
References and Notes 1. 2. 3.
C. Wyss, R. Batra, C. Lehmann, S. Sauer, B. Giese, Angew. Chem. Int. Ed. Engl. 1996, 35, 2529. Synthesis and photocyclization of the modified dipeptides 5, 8, 11, 14, and 16 followed the conditions described in ref. 1. The relative configurations of 6, 7, and 12 were elucidated by NOE experiments. Moreover, the chemical shifts (ill- and 13C-N1VIR)of the CH 3 group are characteristic for the trans- and the cis-pyrrolidinone rings: cis
trans
BOCH~'~N
Ph",~,,,~b BocHN~ / "~ ~, .,,~'~ .N~ 1 ~CO2Bn H3 ,,' C .~A R = H, OH3 1,5-3%
. y ° ~ OsBn R = CH3
Chemical Shifts 8 (ppm) of the CH 3 group at the pyrrolidinone ring trans product
R
~H
13C
cis product
R
JH
13C
19 20 6
H Me Pr i
1.60 1.52 1.39
19.2 18.8 19.0
12,13 21 7
H Me Pr i
0.98 0.89 0.93
22.2 21.7 22.0
Compounds 19-21 are not mentioned in the communication because 19 is formed only in minute amounts '° and 20+21 are formed with only low selectivity from the modified ala-ala dipeptide. The absolute configuration of the trans product 6 is based on the X-ray crystal structure t2 of the trifluoroacetate salt of the protonated trans product 17 and the comparison of NMR data: in general, a methylene proton H,, which is cis to the OH group of the pyrrolidinone ring, absorbs at lower field than a geminal proton H b which is trans to the OH group (data not shown). In addition, the cis proton H~ of 17 (product of,,memory effect") absorbs at lower field (8 = 4.41 ppm) than the cis proton H, of 18 (~5= 4.05 ppm). Similar differences in chemical shifts of H a are also found in the trans photocyclization products from the modified ala-val (8 = 3.80 and 3.68 ppm) and ala-ala (8 = 3.66 and 3.60 ppm) dipeptides. From the trans product 6 a cis carbamate was synthesized by treatment with SOCI 2 which inverted the alcoholic carbon center. This cis carbamate was a diastereomer of the cis carbamate formed directly from 7 by deprotection of the Boc group and cyclization with N,N'-carbodiimide. 4. The photocyclizations of dipeptides 5 and 8 occur also into the isopropyl group of valine. This leads to pyrrolidine derivatives in 11% (from 5) and 36% (from 8), respectively. Diastereomers of 6 and 7, in which the configuration of the alcoholic carbon center is inverted, are formed only in traces. 5. For a discussion of the term ,,memory effect", see: J. C. Scaiano, Tetrahedron 1982, 38, 819; A. G. Griesbeck, H. Mauder, S. Stadtmiiller, Acc. Chem. Res. 1994, 27, 70; K. Fuji, T. Kawabata, Chem. Eur. J. 1998, 4, 373. 6. To our knowledge only two other examples of retention of the stereochemistry in type-II photocyclization reactions of acyclic systems are known: S. Kohmoto, T. Kreher, Y. Miyaji, M. Yamamoto, K. Yamada, J. Org. Chem. 1992, 57, 3490; W. Weigel, S. Schiller, G. Reck, H. G. Henning, Tetrahedron Lett. 1993, 34, 6737. 7. After conformational analysis (MacroModel software, Amber force field, Monte Carlo search method) one finds conformations for 5 and 8 in which the distance between the benzoyl oxygen and the hydrogen at the chiral center of alanine are close enough for H-abstraction (2.6-2.9/~). These calculated conformations are used in Scheme 3 for the photoexcited molecules 5* and 8", see also ref. 1. 8. The photocyclization could be completely prevented by 2,5-dimethylhexadiene as triplet quencher. 9. L . S . Hegedus, E. Lastra, Y. Narukawa, D. C. Snustad, J. Am. Chem. Soc. 1992, 114, 2991. 10. The trans products were formed only in minute amounts. 11. The main cyclization product 17 (from 16) corresponds to the main cyclization product 6 (from 5). However, the minor products 18 and 7 differ from each other by different configurations at the alcohol center. In order to understand these differences, work with other amino acids in different solvents will be carried out. 12. The structure was proven by the X-ray crystal structure of the trifluoroacetate salt of the protonated trans product 17. Crystallographic data have been deposited at the Cambridge Crystallographic Data Centre.
Pergamon
Memory Effect of Chirality in the Photocyclization of Modified Dipeptides
Stefan Sauer, Andreas Schumacher, Fr6d6rique Barbosa and Bernd Giese*
Department of Chemistry, Universityof Basel, St. Johanns-Ring 19, CH-4056 Basel, Switzerland
Received 27 February 1998; accepted 17 March 1998
Abstract: Photocyclizations of dipeptides 5 and 8 occur mainly with retention of configuration at the stereogenic center of alanine. This memory effect of chirality is explained by a hindered rotation in the two intermediate biradicals 9 and 10 that slows down the equilibration of the radicals. © 1998 Elsevier Science Ltd. All rights reserved.
Recently, we have demonstrated that photochemical cyclizations of the modified dipeptides 1 into glycine are regio- and stereoselective and follow a remarkable asymmetric induction if valine is the inducing amino acid. 1 Intermediates are biradicals 2 that are formed in a regioselective H-abstraction step from the triplet state of the phenyl ketone. After the triplet-singlet intersystem crossing the biradical 2 cyclizes and yields 3 as main product.
O,~Ph
HO.~Ph Ph
(~ H2)n hv ~N~ IC02Me 0
R 1
.. .yco2Me
,
0
R
O
R
O
3
2
n=l
Scheme I
HO
(~H2)n
n=2
10
7.4
R
4 :
1 (R=Pr j,51%)
:
1 (R = Pri, 67"/o)
We have now observed that selective photochemical cyclization reactions can occur also if both amino acids of the dipeptides are substituted) Thus, the modified ala-val dipeptide 5 yields mainly pyrrolidinone 6 as cyclization product. 3 The isomer ratio 6:7 of 16:1 at-15°C demonstrates that the C,C-bond formation occurs with high retention at the stereogenic center of alanine. In order to check whether this stereoselectivity is caused by the asymmetric induction of valine we have synthesized the R,S-ala-val dipeptide 8. This dipeptide also cyclized with high stereoselectivity, but now isomer 7 was the main cyclization product (6:7, <1:20, 0°C). Again, the product with retention of configuration at the alanine was formed preferentially.4
0040-4039/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved. PII." S0040-4039(98)00621-2
3686
Ph HO hv
BocHN'~Ny
cO2Bn
O
HC)
B ° c H N ' " " " ~ N ~ C O 2 B n + BocHN~ ~ , , ~I N v C O 2 B n -!
Pri
O
5
0% O
-. Pd
h v i=,
8
:
1 (20°C, CH3OH, 50%)
16
:
1 (-15°C, CH3OH)
4
:
1 (0°C, CH2CI2)
BOCHN'""~Ny c02Bn+= .
O
HO Ph.,..~ BocHN,~ / \ " " ~ / N V C O 2 B. n _
Pd
O
6
Pd
7
1 <1
Scheme 2
15ri
7
HO P h ~
CO2Bn
-
O
6
Ph
BocHN,/~Nv
"
Pd
: :
10 (20°C, CH2CI2,35%) 20 (0°C, CH2CI2)
The experimental results show that the intermediate biradicals formed from dipeptides 5 and 8 must differ from each other during their reaction time scale and that they possess a memory of the configuration of their precursors. A possible explanation of this memory effect5"6is given in Scheme 3: The H-abstraction by the photochemical excited ketone 5 *7 leads to biradical 9 in which the hydroxybenzyl radical is positioned at the
re-
side of the alanyl radical. If the triplet-singlet intersystem crossing 8 and the subsequent radical combination is faster than the rotation around the N - C H 2 bond (9 ~ 10), then the cyclized product 6 with retention of configuration is formed preferentially. In a similar way, dipeptide 8 would yield 7 as main cyclization product.
Ph
Ph
hv 5
( =
hv
pr i
0
H
5*
p i
0
8
~
H
8*
1 HO
/
6
"
BocHN"
""'I ~NI .,,,pri ~J~ " ~ C O 2 B n O H 9
' " ~i N Ph
i ,,,Pr BoeHN"H(~"'~CO2Bn O H
"
7
10
Scheme 3
In biradicals 9 and 10 the rotation around the N - C H 2 bond is presumably hindered by the alkyl substituents of the amino acids. In order to check this we synthesized modified dipeptides 11 and 14 containing
3687
glycine or selectively deuterated glycine9 as one of the amino acids. The photochemical cyclization of 11 led to products 12 and 13 in a l'l ratio, t° Thus, the memory effect of chirality is completely lost. Obviously, the equilibration of the intermediate biradicals is faster than the triplet-singlet interconversion with subsequent cyclization.
Ph O:==~
BocHN~N~
H~h,,.~
P~,?,..~
CO2Bn chHV(~I2B o c H N ~ / N ~ C O 2 Bn + B°cH~ N , ~ J ~ C O 2 B n
O
O
11
12
O 1
:
1
Ph
HO Ph,,,..~-.~ ZHN~ I \
0 HO,,,..~.~r~~ D%~ IN..CO2Bn hv N~,~,/~Nv ZHN" y y CH2CI2 ZH "" C02Bn 0 Pri 0 Pd Scheme4
14
15
10
13
D,~-Nv C02Bn 0
:
1
Pd
16
The photochemistry of selectively deuterated 9 dipeptide 14 is also very instructive. In Scheme 4 only the deuterated cyclization products following the H-abstraction are shown. The preferred formation of the pyrrolidinone 15 is in accord with the asymmetric induction found for the undeuterated dipeptide 1 (Scheme l ) l but the H-abstraction and the C,C bond formation occur on opposite sides of the glycine. This means that the asymmetric induction by valine (1-~3 or 14--->15) and not the memory effect of chirality governs the photocyclization of 14. These experiments offer strong support for the explanation that the memory effect is caused by a hindered rotation around the N-CH 2 bond that slows down the equilibration between 9 and 10. Therefore, the intersystem crossing with subsequent cyclization is faster than the equilibration, and the biradicals 9 and 10 preserve the memory of the alanine chirality. That this memory effect could be a general phenomenon in photocyclizations of substituted peptides with bulky amino acids is demonstrated by the cyclization of dipeptide 16 which led mainly to compound 17 with retention of the chiral center of proline. 11.12 Ph
==•N~CO2Bn
O
,
Boc
,, 0 16
Me
hv / 20°C~ CH C, 50%
Hp~h~,,.. ~~N.,..jCO2Bn+ '0 °
HO=
,,
_ e
17
..y/CO2Bn
(/" I 0
Boc 5
:
1
_, Me
18
Scheme 5
Acknowledgments: This work was supported by the Swiss National Science Foundation. We thank Prof. M. Zehnder and M. Neuburger for the crystal structure analysis and Dr. Pablo Wessig for very helpful discussions.
3688
References and Notes 1. 2. 3.
C. Wyss, R. Batra, C. Lehmann, S. Sauer, B. Giese, Angew. Chem. Int. Ed. Engl. 1996, 35, 2529. Synthesis and photocyclization of the modified dipeptides 5, 8, 11, 14, and 16 followed the conditions described in ref. 1. The relative configurations of 6, 7, and 12 were elucidated by NOE experiments. Moreover, the chemical shifts (ill- and 13C-N1VIR)of the CH 3 group are characteristic for the trans- and the cis-pyrrolidinone rings: cis
trans
BOCH~'~N
Ph",~,,,~b BocHN~ / "~ ~, .,,~'~ .N~ 1 ~CO2Bn H3 ,,' C .~A R = H, OH3 1,5-3%
. y ° ~ OsBn R = CH3
Chemical Shifts 8 (ppm) of the CH 3 group at the pyrrolidinone ring trans product
R
~H
13C
cis product
R
JH
13C
19 20 6
H Me Pr i
1.60 1.52 1.39
19.2 18.8 19.0
12,13 21 7
H Me Pr i
0.98 0.89 0.93
22.2 21.7 22.0
Compounds 19-21 are not mentioned in the communication because 19 is formed only in minute amounts '° and 20+21 are formed with only low selectivity from the modified ala-ala dipeptide. The absolute configuration of the trans product 6 is based on the X-ray crystal structure t2 of the trifluoroacetate salt of the protonated trans product 17 and the comparison of NMR data: in general, a methylene proton H,, which is cis to the OH group of the pyrrolidinone ring, absorbs at lower field than a geminal proton H b which is trans to the OH group (data not shown). In addition, the cis proton H~ of 17 (product of,,memory effect") absorbs at lower field (8 = 4.41 ppm) than the cis proton H, of 18 (~5= 4.05 ppm). Similar differences in chemical shifts of H a are also found in the trans photocyclization products from the modified ala-val (8 = 3.80 and 3.68 ppm) and ala-ala (8 = 3.66 and 3.60 ppm) dipeptides. From the trans product 6 a cis carbamate was synthesized by treatment with SOCI 2 which inverted the alcoholic carbon center. This cis carbamate was a diastereomer of the cis carbamate formed directly from 7 by deprotection of the Boc group and cyclization with N,N'-carbodiimide. 4. The photocyclizations of dipeptides 5 and 8 occur also into the isopropyl group of valine. This leads to pyrrolidine derivatives in 11% (from 5) and 36% (from 8), respectively. Diastereomers of 6 and 7, in which the configuration of the alcoholic carbon center is inverted, are formed only in traces. 5. For a discussion of the term ,,memory effect", see: J. C. Scaiano, Tetrahedron 1982, 38, 819; A. G. Griesbeck, H. Mauder, S. Stadtmiiller, Acc. Chem. Res. 1994, 27, 70; K. Fuji, T. Kawabata, Chem. Eur. J. 1998, 4, 373. 6. To our knowledge only two other examples of retention of the stereochemistry in type-II photocyclization reactions of acyclic systems are known: S. Kohmoto, T. Kreher, Y. Miyaji, M. Yamamoto, K. Yamada, J. Org. Chem. 1992, 57, 3490; W. Weigel, S. Schiller, G. Reck, H. G. Henning, Tetrahedron Lett. 1993, 34, 6737. 7. After conformational analysis (MacroModel software, Amber force field, Monte Carlo search method) one finds conformations for 5 and 8 in which the distance between the benzoyl oxygen and the hydrogen at the chiral center of alanine are close enough for H-abstraction (2.6-2.9/~). These calculated conformations are used in Scheme 3 for the photoexcited molecules 5* and 8", see also ref. 1. 8. The photocyclization could be completely prevented by 2,5-dimethylhexadiene as triplet quencher. 9. L . S . Hegedus, E. Lastra, Y. Narukawa, D. C. Snustad, J. Am. Chem. Soc. 1992, 114, 2991. 10. The trans products were formed only in minute amounts. 11. The main cyclization product 17 (from 16) corresponds to the main cyclization product 6 (from 5). However, the minor products 18 and 7 differ from each other by different configurations at the alcohol center. In order to understand these differences, work with other amino acids in different solvents will be carried out. 12. The structure was proven by the X-ray crystal structure of the trifluoroacetate salt of the protonated trans product 17. Crystallographic data have been deposited at the Cambridge Crystallographic Data Centre.